Discovery of the Novel Potent and Selective FLT3 Inhibitor 1-{5-[7-(3-Morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and Its Anti-Acute Myeloid Leukemia (AML) Activities in Vitro and in Vivo
Discovery of the Novel Potent and Selective FLT3 Inhibitor 1-{5-[7-(3-Morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and Its Anti-Acute Myeloid Leukemia (AML) Activities in Vitro and in Vivo
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DOI：
10.1021/jm300042x
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发表时间：
2012-04-26
影响因子：
7.3
通讯作者：
Yang, Sheng-Yong
中科院分区：
文献类型：
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作者：
Li, Wei-Wei;Wang, Xiao-Yan;Yang, Sheng-Yong
描述了2-（喹唑啉-4-基硫代）噻唑衍生物的结构-活性关系（SAR）研究，其用于优化先前鉴定的FLT 3抑制剂2-（6，7-二甲氧基喹唑啉-4-基硫代）噻唑（1）的体外和体内抗急性髓性白血病（AML）活性。以1的喹唑啉部分的头部（噻唑）和尾部（6位和7位）为中心的SAR研究发现了一系列化合物，其对FLT 3驱动的AML MV 4 -11细胞表现出显著增加的效力。对三个高活性化合物进行了初步的体内活性测定，结果表明1-{5-[7-（3-吗啉代丙氧基）喹唑啉-4-基硫基]-[1，3，4]噻二唑-2-基}-3-对甲苯基脲（20 c）具有最高的体内活性。然后对20 c进行进一步的体外和体内抗AML研究;在MV 4 -11异种移植小鼠模型中，以100 mg/kg每日一次剂量给予20 c，持续18天，导致肿瘤完全消退，无明显毒性。Western blot和免疫组化分析表明20 c的作用机制。
Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly dincreased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.